ABSTRACT Severe pediatric febrile illness has high global mortality and disproportionately affects children in resource- limited settings in sub-Saharan Africa (SSA). Though rapid, appropriate treatment can improve outcomes in severe febrile illness, we lack a robust understanding of how to rapidly identify children in need of urgent and specific management. My central hypotheses are that next generation sequencing can improve detection of a serious bacterial infection compared to culture and that biomarker point-of-care tests can predict a serious bacterial infection and clinical deterioration in children presenting with severe febrile illness. With the Pediatric Severe Infection Collaboration (UCSF, Muhimbili Hospital in Tanzania, and the Chan Zuckerberg Biohub in San Francisco), this proposal leverages expertise that uses clinical data, cutting-edge pathogen detection methods, an innovative bioinformatics platform (Global IDSeq), and biomarkers to develop a treatment algorithm for severe febrile illness in Africa. In this prospective cohort study of Tanzanian children with severe febrile illness, we will determine risk factors associated with poor clinical outcomes (Aim 1) and employ both locally available diagnostic techniques (Aim 1) and state-of-the-art next generation sequencing to determine the etiology of severe febrile illness (Aim 2). Using data from Aims 1 & 2, we will determine which POCTs for host serum biomarkers (procalcitonin, C-reactive protein, ferritin, lactate, blood sugar, and hemoglobin) best predict serious bacterial infection and clinical deterioration (Aim 3) and develop a treatment algorithm incorporating clinical signs and biomarkers that will guide management and resource allocation. My long-term career objective is to improve clinical outcomes for children with severe febrile illness through the development and implementation of evidence-based interventions that are appropriate and context-relevant for resource-limited settings. This Mentored Patient-Oriented Research Career Development Award offers me the opportunity to: (1) develop skills and expertise necessary to become an independent physician-scientist in the field of pediatric severe febrile illness; (2) integrate population-specific clinical data, locally available diagnostic data, cutting-edge next generation sequencing science, and host biomarkers to better identify serious bacterial infections and high-risk children; (3) build further clinical research infrastructure and processes in Tanzania for future clinical studies; and (4) learn and apply next-generation sequencing data analysis using a bioinformatics approach and advanced biostatistical analyses of complex observational data. I have assembled a mentoring, collaborative team with diverse expertise who are committed to helping me achieve these goals. After completion of this proposal that employs local clinical data, a highly sensitive method of pathogen detection, an innovative bioinformatics platform, and a unique approach to risk stratification with point-of-care biomarkers, we will be uniquely positioned to create an evidence-based, context?specific treatment algorithm to improve outcomes in children with severe febrile illness in SSA, which will be tested in an R01-funded study.